3-芳基-5-三氮唑基-噁二唑衍生物HIF-1抑制剂的设计、合成与构效关系研究

Design, Synthesis and Structure-activity Relationship Study of 3-Aryl-5-triazolyl-oxadiazole Derivatives as Hypoxia-inducible Factor-1 Inhibitors

关键词:  缺氧诱导因子-1  抑制剂  3-芳基-5-三氮唑基-噁二唑衍生物  构效关系  肿瘤转移

Key words:  HIF-1  inhibitor  3-aryl-5-triazolyl-oxadiazoles derivatives  structure-activity relationship  tumor metastasis

摘要:

目的 设计、合成3-芳基-5-三氮唑基-噁二唑类缺氧诱导因子-1(hypoxia-inducible factor 1，HIF-1)抑制剂。方法 以化合物8为先导，将吡唑基替换为1,2,3-三氮唑基，并对噁二唑和苯环取代基等进行改造，获得全新的3-芳基-5-三氮唑基-噁二唑衍生物。结果 所合成的大部分化合物均显示出较优的HIF-1抑制活性，化合物10n活性最强，IC₅₀值为0.59 μmol·L^-1，其作用机制是抑制HIF-1α蛋白表达，且能显著抑制SKOV3细胞的侵袭和迁移。结论 设计、合成的3-芳基-5-三氮唑基-噁二唑类衍生物是全新的HIF-1抑制剂，显示出抑制肿瘤迁移的效应。

Abstract:

OBJECTIVE To design and synthesize a series of 3-aryl-5-triazolyl-oxadiazole derivatives as hypoxia- inducible factor 1(HIF-1) inhibitors. METHODS Taking compound 8 as the guide, the pyrazolyl group was replaced with 1,2,3-triazole group, and the oxadiazole and benzene ring substituents were modified to obtain a novel series of 3-aryl-5-triazole group oxadiazole derivatives. RESULTS Most of these newly designed compounds showed good HIF-1 inhibitory activities and compound 10n was the most potent inhibitor with IC₅₀ value of 0.59 μmol·L^-1. Its mechanism of action was to inhibit the expression of HIF-1α protein, and could significantly inhibit the invasion and migration of SKOV3 cells. CONCLUSION The series of 3-aryl-5-triazolyl-oxadiazole derivatives are new HIF-1 inhibitors, showing the effect of inhibiting tumor migration.